(1) Field of the Invention
The present invention relates to the use of calcium channel blocker compounds, known for use in the treatment of cardiovascular disorders, such as hypertension, angina and arrhythmia, for the inhibition of tumor growth and metastasis. In particular, the present invention preferably relates to the use of nimodipine (BAY e 9736) and nifedepine (Bay a 1040) and structurally related compounds for such inhibition; however, many other calcium channel blocker compounds can be used.
(2) Prior Art
The primary focus of cancer therapy and research has been directed towards the treatment of the initial or primary tumor. Considerable success has been achieved by utilizing surgery, radiotherapy, and/or chemotherapy. However, it has become increasingly apparent that metastasis, the spread of cancer from the initial tumor to other physically separate sites in the body, is an equally life-threatening situation that must be confronted. The exact steps of metastasis are not known, but it has been proposed, and to a certain extent demonstrated, that the entrapment or adhesion of loosened tumor cells of the primary tumor circulating in the vasculatory or lymphatic systems to endothelial substrate in the systems may be an important step of the metastatic cascade.
The metastatic cascade can be described as a sequence of events, that a tumor cell or cells must successfully complete in order to become a metastatic foci. Although different authors vary somewhat in their terminology, the cascade can be thought of as four sequential stages or steps (Weiss, L. In: Fundamental Aspects of Metastasis. pp. 1-5, 1976; Fidler, I. J., Methods Cancer Res. 25:399-439, 1978; and Clark, R. L. Cancer 43:790-797, 1979). First, a tumor cell or clump of tumor cells must be "shed" by the primary tumor. Second, the tumor cells must enter the vascular or lymphatic system and avoid destruction by host immune defenses (macrophages, natural killer cells, immune complexes, etc.). Third, the tumor cells must adhere to the endothelial lining of the vascular or lymphatic system. Fourth, the adhering tumor cells must avoid dislodgement, extravasate through the endothelium and divide. Tumor cell interactions with host platelets to form a tumor cell-platelet aggregate or thrombus has been proposed as a possible mechanism that would allow tumor cells to successfully complete the last stages of the metastatic cascade.
Platelet aggregation and adhesion are typically thought to be initiated by a number of soluble and non-soluble factors including catecholamines, prostaglandins, immune complexes, complement components, ADP, and collagen (Gordon, J. L. In: Platelets in Biology and Pathology - 2. J. L. Gordon, ed., Elsevier North Holland Biomedical Press, Amsterdam, pp. 1-7, 1981; Weiss, H. J. In: Platelets: Pathophysiology and Antiplatelet Drug Therapy. Alan R. Liss, Inc., New York pp. 13-17, 1982; and Jamieson, G. A., Bastida, E. and Ordinas, A. In: Interaction of Platelets and Tumor Cells. G. A. Jamieson, ed., Alan R. Liss, Inc., New York, pp. 405-413). Additionally, it has been demonstrated that tumor cells can induce platelet aggregation (Gasic, G. J., Gasic, T., Galanti, N., Johnson, T. and Murphy, S. Int. J. Cancer 11:704-718, 1973; Hara, H., Steiner, M. and Baldini, M. G. Cancer Res. 40:1217-1222, 1980; and Bastida, E., Ordinas, A. and Jamieson, G. A. Nature 291-: 661-662, 1981). It is possible that the resultant tumor cell-platelet thrombus could protect or shield the tumor cells from attack by the host immune system, increase the likelihood that the tumor cells would adhere to the endothelial lining of the vascular system, and protect adhering tumor cells from dislodgement. Thus, pharmacological agents that inhibit platelet aggregation or reduce platelet number have been investigated for their ability to suppress metastasis (Gasic, G. J., Gasic, T. B. and Steward, C. C. Proc. Natl. Acad. Sci. USA 61:46-52, 1968; Honn, K. V., Cicone, B. and Skoff, A. Science 212:1270-1272, 1981; and Menter, D., Neagos, G., Dunn, J., Palazoo, R., Tchen, T. T., Taylor, J. D. and Honn, K. V. In: Prostaglandins and Cancer. First Intl. Conf., pp. 809-813, 1982).
Platelet aggregation is usually thought of as a sequential process involving "primary" platelet aggregation, which consists of the direct interaction of an aggregating agent with its specific receptor on the platelet surface (Mustard, J. F. and Rackham, M. A. Pharmac. Rev. 22:97-107, 1970; and Mills, D. C. and MacFarlane, D. E. In: Platelets in Biology and Pathology. J. L. Gordon, ed., North Holland Press, New York, pp. 159-163, 1976), and "secondary" platelet aggregation which may involve the release of storage granules and the influx of extracellular calcium (Meyers, K. M., Seachord, C. L., Holmsen, H., Smith, J. B. and Prieur, D. J. Nature 282:331-333, 1979; Shaw, J. O. and Lyons, R. M. Biochim. Biophys. Acta 714:492-499, 1982; and Imai, A., Kawai, K. and Nozawa, Y. Biochem. Biophys. Res. Commun. 108:(2)752-759, 1982). While there is still some debate as to the specific platelet processes involved in primary as opposed to secondary platelet aggregation, an intraplatelet increase in calcium ion (Ca .sup.++) and an influx of extracellular calcium are definitely involved in platelet aggregation, and perhaps even serve as triggering mechanisms (Kao, K. J., Sommer, J. R. and Pizzo, S. V. Nature 292:(5818)82-84, 1981; Gerrard, J. M., Peterson, D. A. and White, J. G. In: Platelets in Biology and Pathology - 2. J. L. Gordon, ed., North Holland Biomedical Press, Amsterdam, pp. 407-436, 1981: Rittenhouse-Simmons, S. J. Biol. Chem. 256:(9)4153-4155, 1981; Shukla, S. D. Life Sciences 30:1323-1335, 1982; Serhan, C. N., Fridovish, J., Goetzel, E. J., Dunham, P. B. and Weissman, G. J. Biol. Chem. 257:(9)4746-4752, 1982; Gorman, R. R. Fed. Proc. 38:(1)83-88, 1979; and Parise, L. V., Venton, D. L. and Lebreton, G. D. J. Pharm. Exptl. Therap. 222:(1)276-281, 1982). Thus, the recent reports that calcium channel blockers can inhibit platelet aggregation induced by ADP or epinephrine are not surprising. Circulation 62 (Suppl. III Abstracts No. 1123, 1258) Abstract of 53rd Scientific Sessions 62 Suppl III October 1980.
Calcium ions function as extracellular and intracellular messengers and regulating agents to control myriad physiological functions. The control of platelet aggregation is only one small regulatory function of calcium. Clinically, one of the most important functions is its regulation of muscle contraction. Within the past two decades the concept has developed that the blocking of calcium effects could be clinically useful in the treatment of disorders resulting from restricted blood flow (through vascular, pulmonary, and/or coronary arteries) and from arrhythmias (abnormalities in the contractions of the heart).
An increase in intracellular Ca .sup.++ triggers contraction in both the smooth muscle tissue of the arteries and the cardiac muscle tissue of the heart. In both types of muscle tissue, the entry of Ca .sup.++ triggers interactions between two proteins, actin and myosin, leading to cellular contraction, and is responsible for the contractions of the heart and the diameter and flow rate of blood through arteries. Although the muscle cells of the heart and arteries contain structures which store and release Ca .sup.++ it is the entry of Ca .sup.++ from outside the muscle cells through selective sites in the cell membrane, the so-called "calcium channels," which trigger muscle contraction. Because of selective imbalances in positively and negatively charged ions between the inside and the outside of all cells of the body, there exists an electrical charge difference, measurable in millivolts across living cell membranes, including muscle cell membranes. The calcium channels are normally closed in the resting muscle cell, and open to permit the entry of Ca .sup.++ into the muscle cells only during depolarization of the muscle cell membrane (i.e., a reversal of polarity across the muscle cell membrane).
Although there are structures in the muscle cell membrane that regulate the opening and closing of the calcium channel independent of depolarization, and certain ions such as manganese and cobalt can keep the calcium channels closed, these factors all are non-specific in that they affect other cellular functions.
Organic calcium channel blockers are highly specific and can exert their effects in nanomolar concentrations. The primary work of Fleckenstein A., Am. Rev. Pharmacol. Toxicol. 17:149-166 (1977) determined that these compounds could selectively blockade the calcium channels and electrical functions of muscle tissue. Calcium channel blockers may function by actually "plugging" the "closed" channel of the resting muscle cell membrane (nimodipine and nifedipine), or they may interact with the "open" calcium channel during depolarization (verapamil and diltiazem). The "open" channel blockers function best during muscular contraction.
A number of vascular and myocardial disorders can be alleviated by inducing vasodilation by calcium channel blocker treatment (i.e., relaxation of arterial smooth muscle which results in increased blood flow). These include: (1) vasospastic angina, including Prenzmetal's angina; (2) stable (effort-induced) angina; (3) acute myocardial infraction; (4) surgically induced myocardial arrest; (5) arrhythmias; (6) systemic hypertension; (7) pulmonary hypertension; (8) congestive heart failure; (9) hypertrophic cardiomyopathy. All of these disorders have in common a decrease in blood flow or availability and as a common relief, an increase or easing of blood flow which can be induced by the vasodilating effects of calcium channel blockers.
Many compounds are known to function as an antimetastatic agent using different mechanisms for interrupting the metastatic cascade. We, as well as others, have proposed and demonstrated that tumor metastasis is enhanced by tumor cell interactions with platelets and that agents which block or prevent tumor cell-platelet interaction and aggregation have antimetastatic effects. Agents which have been investigated function by reducing platelet cell number in the blood or by inhibiting platelet function (aggregation). Pending U.S. patent application Ser. No. 420,642, filed Sept. 21, 1982 by one of the inventors herein jointly with others describes nafazatrom, an anticoagulant, which is used as an antitumor and antimetastatic agent.